Synthesis of Poly(acyclic orthoester)s: Acid‐Sensitive Biomaterials for Enhancing Immune Responses of Protein Vaccine

Abstract

While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over poly(lactic-co-glycolic acid) (PLGA) nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research.

Intelligent stimuli-responsive nano immunomodulators for cancer immunotherapy

“…Xing et al 50 utilized an acid-activatable polymer with a common pH-labile bond, the hydrazone bond, to present antigens and adjuvants to antigen-presenting cells (APCs) for eliciting tumor-specific immunity. In another study, Guo and co-workers 51 developed acid-labile nanoparticles with the acid-sensitive poly(acyclic orthoester)s to specifically release a protein vaccine to enhance the immune responses. In addition, Jiang et al 52 designed size-variable nanoparticles to mediate the polarization of the macrophage to reshape the tumor immune microenvironment for enhanced immunotherapy ( Fig.…”

Leveraging the Modularity of Biomaterial Carriers to Tune Immune Responses

“…Faster release under acidic conditions enhances antigen presentation [83] Delivery of immunostimulatory cues…”

“…Faster release under acidic conditions enhances antigen presentation [83] Delivery of immunostimulatory cues Shape Computationally designed nucleic acid sequences that self-assemble into 2D and 3D structures Inflammatory cytokine secretion can be tuned based on dimensions (i.e., 2D vs 3D), and the number of sides on polygonal structures [91,95] Conjugating poorly immunogenic RNA adjuvant to gold NP Nanorods improve adjuvanticity [109] Controlled release Materials selection: polymers degradable by hydrolysis or degraded under acidic conditions Products of polymer degradation can modulate immune activity [96][97][98] Alter binding affinity of polymer to TLRa by using softer chained polymers or varying polymer:TLRA ratio Reduction in adjuvanticity of TLRa with increased interaction strength of polymer carrier [113,114] Surface functionalization (ligand density)…”

“…For example, poly(orthoester)s that rapidly degraded at pH 5.0 were found to enhance antigen presentation over PLGA NPs, suggesting that faster release kinetics improved antigen processing. [ 83 ] Additionally, the accumulation of particles within immune cells can pose problems. Accumulation of particles can lead to endosomal dysfunction, leading to blockage of other key cellular functions.…”

Degradation in Order: Simple and Versatile One‐Pot Combination of Two Macromolecular Concepts to Encode Diverse and Spatially Regulated Degradability Functions

“…Thea pproach is also more facile and straightforward than recently reported synthetic procedures to prepare polyesters with acid-sensitive ortho-ester groups along the chains. [17]…”